Selective control of SIRP-α–positive airway dendritic cell trafficking through CD47 is critical for the development of T_H2-mediated allergic inflammation

Background

Dendritic cells (DCs) are essential for the initiation and maintenance of T_H2 responses to inhaled antigen that lead to the establishment of allergic diseases. Two subpopulations of nonplasmacytoid DCs (ie, CD11b^lowCD103⁺ and CD11b^highCD103^-) are found in lung/airway tissues. Yet the identification and migratory properties of the DC subset that contributes to T_H2-mediated responses remain to be clarified. CD47, a signal regulatory protein (SIRP)–α partner, reportedly governed skin DC migration.

Objective

We here thought to investigate the role of CD47/SIRP-α interactions in airway DC trafficking and the development of allergic airway inflammation.

Methods

We characterized the DC influx into lungs and mediastinal lymph nodes in CD47^-/- and CD47^+/+ BALB/c mice by using experimental models of allergic asthma. Mice were systemically (intraperitoneal ovalbumin/alum) or locally (intratracheal ovalbumin-loaded bone marrow–derived DCs) immunized and challenged by ovalbumin aerosol. We also evaluated the consequences of SIRP-α-Fc fusion molecule administration on the induction of airway disease in BALB/c mice.

Results

SIRP-α selectively identified the CD11b^highCD103^- DC subset that predominantly accumulated in mediastinal lymph nodes during airway inflammation. However, CD103^-SIRP-α⁺ DC trafficking, T_H2 responses, and airway disease were impaired in CD47^-/- mice. Importantly, the adoptive transfer of CD103^- SIRP-α⁺CD47^+/+ but not CD47^-/- DCs elicited a strong T_H2 response in CD47^-/- mice. Finally, the administration of SIRP-α-Fc molecule protected BALB/c mice from allergic airway inflammation.

Conclusion

Lung CD11b^highCD103^-SIRP-α⁺ DC migration is governed by self-CD47 expression, and manipulation of the CD47/SIRP-α pathway suppresses CD103^-SIRP-α⁺ DC-driven pathogenic T_H2 responses and airway inflammation.

Key words: Dendritic cells, migration, CD103, allergic inflammation, T_H2, CD47, SIRP-α

Abbreviations used: BALF, Bronchoalveolar lavage fluid, BMDC, Bone marrow–derived dendritic cell, DC, Dendritic cell, FITC, Fluorescein isothiocyanate, Foxp3, Forkhead box protein 3, LN, Lymph node, MFI, Mean fluorescence intensity, mLN, Mediastinal lymph node, pDC, Plasmacytoid dendritic cell, SIRP, Signal regulatory protein